Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa.

We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Nature communications. 2016 Apr 07*** epublish ***

Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W Long, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Wei Zheng, Curtis A Pettaway, Edward D Yeboah, Yao Tettey, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P Chokkalingam, Esther M John, Adam B Murphy, Lisa B Signorello, John Carpten, M Cristina Leske, Suh-Yuh Wu, Anslem J M Hennis, Christine Neslund-Dudas, Ann W Hsing, Lisa Chu, Phyllis J Goodman, Eric A Klein, John S Witte, Graham Casey, Sam Kaggwa, Michael B Cook, Daniel O Stram, William J Blot, Rosalind A Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Melissa C Southey, Liesel M Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L J Tammela, Børge G Nordestgaard, Tim J Key, Ruth C Travis, David E Neal, Jenny L Donovan, Freddie C Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K Dieffenbach, Volker Arndt, Jong Y Park, Thomas A Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A Clements, Manuel R Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, PRACTICAL consortium , David V Conti, Demetrius Albanes, Christine Berg, Sonja I Berndt, Daniele Campa, E David Crawford, W Ryan Diver, Susan M Gapstur, J Michael Gaziano, Edward Giovannucci, Robert Hoover, David J Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R Schumacher, Alkes L Price, Matthew L Freedman, Christopher A Haiman, Bogdan Pasaniuc

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Chan School of Public Health, Boston, Massachusetts 02115, USA., Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California 90095, USA., Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California 90095, USA., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA., Department of Preventative Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA., University of Arizona College of Medicine and University of Arizona Cancer Center, Tucson, Arizona 85721, USA., Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA., Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan 48202, USA., Department of Preventive Medicine, Stony Brook University, Stony Brook, New York 11794, USA., James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, Maryland 21205, USA., Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA., Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA., Korle Bu Teaching Hospital, Accra, Ghana., Korle Bu Teaching Hospital, Accra, Ghana., Korle Bu Teaching Hospital, Accra, Ghana., Korle Bu Teaching Hospital, Accra, Ghana., Korle Bu Teaching Hospital, Accra, Ghana., Westat, Rockville, Maryland 20850, USA., Westat, Rockville, Maryland 20850, USA., School of Public Health, University of California, Berkeley, California 94720, USA., Cancer Prevention Institute of California, Fremont, California 94538, USA., Department of Urology, Northwestern University, Chicago, Illinois 60611, USA., Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. 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Chan School of Public Health, Boston, Massachusetts 02115, USA., Department of Epidemiology, Regional Health Authority, Murcia 30009, Spain., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland 21287, USA., Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK., Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK., Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA., Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. 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